Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL-Induced Evasion of Apoptosis in Part Through Regulation of Forkhead Tumor Suppressors

摘要

BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). Even though ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of BCR-ABL. Here we show that BCR-ABL stimulates the proteasome-dependent degradation of members of the Forkhead family of tumor suppressors in vitro, in an in vivo animal model, and in samples from patients with BCR-ABL-positive CML or ALL. As several downstream mediators of BCR-ABL are regulated by the proteasome degradation pathway, we also demonstrate that inhibition of this pathway, using bortezomib, causes regression of CML-like disease. Bortezomib treatment led to inhibition of BCR-ABL-induced suppression of FoxO proteins and their pro-apoptotic targets, TNF-Related Apoptosis Inducing Ligand (TRAIL) and BIM, thereby providing novel insights into the molecular effects of proteasome inhibitor therapy. We additionally show sensitivity of imatinib resistant BCR-ABL T315I cells to bortezomib. Our data delineates the involvement of FoxO proteins in BCR-ABL-induced evasion of apoptosis and provides evidence that bortezomib is a candidate therapeutic in the treatment of BCR-ABL-induced leukemia.